Phosphoinositide 3-kinase (PI3K) belongs to a large family of lipid signaling kinase that plays key role in cellular processes, including cell growth, differentiation, migration and apoptosis. PI3K family is divided to three classes, I, II and III, based on sequence homology and lipid substrate specificity. Among them, Class I PI3K, which includes PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, is most studied.
Class I PI3K is a heterodimer formed by two subunits, a catalytic subunit (p110) and a regulatory subunit (p85). The catalytic subunit, p110, has four isotypes, α, β, γ, and δ. The p110α has a role in insulin-dependent signaling, p110β in platelet aggregation, thrombosis and insulin signaling, and p110γ and p110δ are expressed mainly in leukocytes and have roles in lymphocyte activation, mast cell degranulation, and chemotaxis. The catalytic p110 subunit associates with p85 regulatory subunit. Upon reception of upstream activation signals, the p85 regulatory subunit releases its inhibition of p110, such that p110 can interact with the lipid membranes to phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) at the 3′-OH position of the inositol ring to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), which then activates downstream signals, resulting in dysregulation of metabolism and protein synthesis, and cell growth, proliferation and survival.
All four class I catalytic PI3K isoforms show a characteristic expression pattern in vivo. p110α and p110β are expressed ubiquitously in mammalian tissue, while p110γ and p110δ appear to be more selectively expressed in leukocyte, endothelial cells and smooth muscle cells. Deletion of the p110α or p110β induces embryonic lethality. p110γ-deficient mice develop and reproduce normally, although they have suboptimal immune responses because of defects in T-cell activation as well as in neutrophil and macrophage migration. The loss of p110δ mice are also viable and fertile but exhibit significant defects in T, B cell activation.
The PI3K pathway is commonly deregulated in cancer cells. The expression of PI3Kδ is generally restricted to hematopoietic cell types. The p110δ isoform is constitutively activated in B cell tumors, and inactivation of it have demonstrated its important role for treatment of B cell malignancy. It's demonstrated that the PI3Kδ plays a critical role in the signaling pathways of various types of leukemia. Hence, it has become an attractive target for pharmacotherapy. Preclinical data on acute myeloid leukemia and chronic lymphocytic leukemia has identified the PI3Kδ as predominant isoform in these diseases. Therefore, a compound having an inhibitory activity on PI3K will be useful for the prevention and treatment of cancer.
In addition to cancer, PI3K has also been suggested as a target for inflammatory and autoimmune disorders.
Although PI3K inhibitors were disclosed in the arts, e.g. WO 2012146666, WO 2003035075 and US 20110015212, many suffer from short half-life or toxicity. Therefore, there is a need for new PI3K inhibitors that have at least one advantageous property selected from potency, stability, selectivity, toxicity and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases. In this regard, a novel class of PI3K inhibitors is provided herein.